tbuckley/cabot-search huggingface dataset:
DIPG-07. Preclinical and case study results underpinning the phase II clinical trial testing the combination of ONC201 and paxalisib for the treatment of patients with diffuse midline glioma (NCT05009992)
Authors: Matthew D Dun, Evangeline R Jackson, Ryan J Duchatel, Mika L Persson, Abdul Mannan, Sridevi Yadavilli, Sarah Parackal, Shaye Game, Wai Chin Chong, Samantha Jayasekara, Marion Le Grand, Padraic S Kearney, Alicia M Douglas, Izac J Findlay, Dilana Staudt, Zacary P Germon, David A Skerrett-Byrne, Brett Nixon, Nathan D Smith, Esther Hulleman, Bryan Day, Geoff B McCowage, Frank Alvaro, Sebastian M Waszak, Martin R Larsen, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicholas A Vitanza, Javad Nazarian, Carl Koschmann, Jason Cain, Sabine Mueller
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline gliomas (DMG), including those of the brainstem (diffuse intrinsic pontine glioma - DIPG), are pediatric CNS tumors recognized as the most lethal of all children’s cancers. Palliative radiotherapy is the only approved treatment, with survival just 9-11–months post-diagnosis. ONC201 shows preclinical and emerging clinical efficacy in early-stage clinical trials, extending survival of DIPG patients by ~9-11–months compared to historic controls. However, patients invariably develop resistance, with some patients completely refractory to treatment. Using a multi-omics approach, including pharmacology, proteomics, genomics, epigenetics, in vitro and in vivo modeling, across ten international laboratories, we have uncovered the inherent mechanisms of resistance to ONC201. We find ONC201 elicits antagonism of the Dopamine receptor D2 (DRD2), whilst also causing mitochondrial degradation through potent agonism of the Mitochondrial protease CLPP, that drives proteolysis of the electron transport chain (ETC) protein Succinate dehydrogenase A (SDHA) and degradation of critical mitochondrial tricarboxylic acid (TCA) cycle regulator Isocitrate dehydrogenase 3B (IDH3B). Loss mitochondrial respiration increased hypoxia and reduced α-ketoglutarate, inhibiting lysine demethylation, increasing methylation of H3K4me3 and H3K27me3, thus altering the epigenome of primary DIPG cells. Loss of SDHA caused oxidation of succinate forming superoxide driving redox regulated PI3K/AKT signaling, counteracted using the PI3K/AKT inhibitor paxalisib. The combination of ONC201 and paxalisib synergically extended survival of two aggressive DIPG PDX models (SU-SIPG-VI vehicle=73 vs. combination=100-days, p=0.0027; SF8626 vehicle=36 vs. combination=43-days, p=0.0002). Compassionate access to this combination (n=2 patients; immediately post-RT and following re-RT) resulted in reductions in tumor volume and complete resolution of disease symptoms, extending overall survival (e.g., diagnosis patient MR axial scan=1554 mm2 , following eight months on the combination, current tumor volume=464 mm2 (&amp;lt;70%), patient remains on treatment). Our findings harness the powerful anti-DMG/DIPG pharmacokinetic/dynamic properties of ONC201 and paxalisib, a combination that is currently in clinical trials (NCT05009992).
Immune cell infiltration of testicular germ cell tumors – a clinical approach
Authors: F. Dittmar, J. Heyer, M. Figura, R. Islam, K. Hartmann, S. Kliesch, F. Wagenlehner, M. Hedger, B. Loveland, K. Loveland, D. Fietz, H-C. Schuppe
Journal: European Urology (2022)
MEDB-03. Medulloblastoma cerebrospinal fluid reveals hypoxic indicators (metabolites and lipids) and cancer-specific RNAs
Authors: Bongyong Lee, Iqbal Mohamad, Rudramani Pokhrel, Rabi Murad, Menglang Yuan, Stacie Stapleton, Chetan Bettegowda, George Jallo, Charles G Eberhart, Timothy Garrett, Ranjan J Perera
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. There has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with MB. CSF samples from patients with (n=40) or without (n=11; no cancer) MB were subjected to RNA-sequencing and high-resolution mass spectrometry to identify RNA, metabolite, and lipid profiles. Differentially expressed transcripts, metabolites, and lipids were identified and their biological significance assessed by pathway analysis. Multivariate analysis method DIABLO (R package mixOmics) was used to integrate the molecular changes characterizing the CSF of MB patients. Differentially expressed transcripts, metabolites, and lipids in CSF were discriminatory for the presence of MB but not the exact molecular subtype. One hundred ten genes and ten circular RNAs were differentially expressed in MB CSF compared to normal representing TGF-β signaling, TNF-a signaling via NF-kB, and adipogenesis pathways. Tricarboxylic acid cycle and other metabolites (malate, fumarate, succinate, α-ketoglutarate, hydroxypyruvate, N-acetyl-aspartate) and total triacylglycerols were significantly upregulated in MB CSF compared to normal CSF. Although the transcriptomic, metabolomic, and lipid signatures in CSF to differentiate MB subgroup separation was challenging, we were able to identify a group of omics signatures that could separate cancer from normal CSF. Metabolic and lipidomic profiles both contained indicators of tumor hypoxia. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.
Non-small cell lung cancer disparities in stage at presentation and treatment status for Asian American, Native Hawaiian, and Pacific Islander females.
Authors: Ji Hyun Hong, Miranda Lam, Edward Christopher Dee, Nishwant Swami
Journal: Journal of Clinical Oncology (2022)

e18526 Background: Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPI) represent the fastest-growing racial group in the United States. While often described in aggregate as one of the healthiest populations, large variations in the social determinants of health and subsequent health outcomes exist within the AANHPI community. We identified differences in stage at presentation and treatment status among AANHPI women with non-small cell lung cancer. Methods: Between 2004 and 2016, a retrospective cohort study was performed using the National Cancer Database (NCDB) with 522,361 female patients with newly diagnosed non-small cell lung cancer (NSCLC). Asian subgroups were distinguished as Chinese, Japanese, Filipino, Hawaiian, Korean, Vietnamese, Laotian, Hmong, Kampuchean, Thai, Asian Indian, Pakistani, and Pacific Islander. Multivariable logistic regression models were used to define adjusted odds ratios (aORs) with 95% CI of presenting at stage IV disease and not receiving treatment. Effect measure modification (EMM) by age was also analyzed in all models. Results: Among 522,361 women, AANHPI women were more likely to present with stage IV disease at presentation when compared to White women (54.32% vs 40.28%, aOR = 1.54, 95%CI = 1.45-1.64, p &lt; 0.001). All AANHPI subgroups also had greater odds of presenting with stage IV diseases when compared to White populations: Chinese (aOR = 1.49, 95%CI = 1.38-1.61, p &lt; 0.001), Japanese (aOR = 1.22, 95%CI = 1.09-1.37, p &lt; 0.001), Filipino (aOR = 1.63, 95%CI = 1.49-1.78, p &lt; 0.001), Korean (aOR = 1.49, 95%CI = 1.30-1.70, p &lt; 0.001), Vietnamese (aOR = 1.74, 95%CI = 1.54-1.97, p &lt; 0.001), Laotian (aOR = 2.24, 95%CI = 1.49-3.37, p &lt; 0.001), Kampuchean (aOR = 1.61, 95%CI = 1.06-2.46, p = 0.027), Thai (aOR = 1.64, 95%CI = 1.17-2.31, p = 0.004), Asian Indian (aOR = 1.50, 95%CI = 1.30-1.73, p &lt; 0.001), and Pacific Islander (aOR = 1.50, 95%C = 1.20-1.88, p &lt; 0.001). In EMM analysis, Asian women aged younger &lt; 65 years were more likely to present with stage IV diseases (p = 0.030 for interaction). Asian women were also more likely not to receive treatment (7.01% vs. 8.80%, 95%CI = 0.84-1.09, p = 0.497). Vietnamese women (aOR = 1.30, 95%CI = 1.06-1.58, p = 0.010) showed significant differences compared to White women. Conclusions: Differences in stage at presentation and treatment status in women with NSCLC were observed among AANHPI subgroups when populations were disaggregated. Efforts are needed to elucidate the barriers these populations face that may explain the observed delays in diagnosis. Further disaggregated study of AANHPI subpopulations is needed to reduce inequities in lung cancer.
Prolonged disease control with pazopanib following radiation of primary tumor for locally advanced and metastatic soft tissue sarcoma.
Authors: Minggui Pan, Jeanette C Yu, Manpreet Kaur Sidhu
Journal: Journal of Clinical Oncology (2022)

e23563 Background: Pazopanib is approved for second or later line therapy for advanced soft tissue sarcoma (STS). Whether or not Pazopanib and radiation have cooperative effect remains unclear. Methods: We retrospectively reviewed 10 patients with locally advanced or metastatic soft tissue sarcoma treated with pazopanib either at the start of radiation or within 4 weeks after the start of radiation. Results: Seven patients were females and age ranged 39-80. Four patients had undifferentiated pleomorphic sarcoma (UPS), two leiomyosarcoma (LMS), two synovial sarcoma (SS), and two dedifferentiated liposarcoma (DDLS). All patients had a large primary tumor that was unresectable with or without distant metastasis. The disease burden with the distant metastasis was low for patients with metastatic disease. Radiation was delivered to the large primary tumor with dose ranging from 15 to 50 Gy (median dose 30 Gy). Pazopanib dose ranged from 400 to 800 mg (majority received 600-800 mg). Eight patients had received one to two lines of chemotherapy previously. Three patients whose pazopanib treatment is still ongoing with stable disease (SD) at 4 (UPS), 25 (LMS), and 26 (DDLS) months respectively. One patient (UPS) with SD discontinued Pazopanib after 3.5 months due to liver toxicities. One patient with SS obtained PR that lasted for 11 months and one patient with SS had SD for 12 months. One patient with relapsed abdominal DDLS obtained a PR followed by resection of residual tumor 8 months after the start of Pazopanib, however, disease relapsed again 3 months after the resection. Three other patients had SD for 8, 8 and 13 months respectively. Conclusions: Our results suggest that Pazopanib at the start or within 4 weeks of radiation in palliative dose can achieve prolonged disease control for patients with locally advanced or metastatic STS. This approach can be considered for selective STS patients with large primary tumor and low distant disease burden.
Deep learning DCE-MRI parameter estimation: Application in pancreatic cancer
Authors: Tim Ottens, Sebastiano Barbieri, Matthew R. Orton, Remy Klaassen, Hanneke W.M. van Laarhoven, Hans Crezee, Aart J. Nederveen, Xiantong Zhen, Oliver J. Gurney-Champion
Journal: Medical Image Analysis (2022)

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an MRI technique for quantifying perfusion that can be used in clinical applications for classification of tumours and other types of diseases. Conventionally, the non-linear least squares (NLLS) methods is used for tracer-kinetic modelling of DCE data. However, despite promising results, NLLS suffers from long processing times (minutes-hours) and noisy parameter maps due to the non-convexity of the cost function. In this work, we investigated physics-informed deep neural networks for estimating physiological parameters from DCE-MRI signal-curves. Three voxel-wise temporal frameworks (FCN, LSTM, GRU) and two spatio-temporal frameworks (CNN, U-Net) were investigated. The accuracy and precision of parameter estimation by the temporal frameworks were evaluated in simulations. All networks showed higher precision than the NLLS. Specifically, the GRU showed to decrease the random error on ve by a factor of 4.8 with respect to the NLLS for noise (SD) of 1/20. The accuracy was better for the prediction of the ve parameter in all networks compared to the NLLS. The GRU and LSTM worked with arbitrary acquisition lengths. The GRU was selected for in vivo evaluation and compared to the spatio-temporal frameworks in 28 patients with pancreatic cancer. All neural network approaches showed less noisy parameter maps than the NLLS. The GRU had better test-retest repeatability than the NLLS for all three parameters and was able to detect one additional patient with significant changes in DCE parameters post chemo-radiotherapy. Although the U-Net and CNN had even better test-retest characteristics than the GRU, and were able to detect even more responders, they also showed potential systematic errors in the parameter maps. Therefore, we advise using our GRU framework for analysing DCE data.
Man vs. machine: A meta-analysis on the added value of human support in text-based internet treatments (“e-therapy”) for mental disorders
Authors: J.A. Koelen, A. Vonk, A. Klein, L. de Koning, P. Vonk, S. de Vet, R. Wiers
Journal: Clinical Psychology Review (2022)

Guided internet-based treatment is more efficacious than completely unguided or self-guided internet-based treatment, yet within the spectrum of guidance, little is known about the added value of human support compared to more basic forms of guidance. The primary aims of this meta-analysis were: (1) to examine whether human guidance was more efficacious than technological guidance in text-based internet treatments ("e-therapy") for mental disorders, and (2) whether more intensive human guidance outperformed basic forms of human guidance. PsycINFO, PubMed and Web of Science were systematically searched for randomized controlled trials that directly compared various types and degrees of online guidance. Thirty-one studies, totaling 6215 individuals, met inclusion criteria. Results showed that human guidance was slightly more efficacious than technological guidance, both in terms of symptom reduction (g = 0.11; p < .01) and adherence (0.26 < g < 0.29; p's < 0.01). On the spectrum of human support, results were slightly more favorable for regular guidance compared to optional guidance, but only in terms of adherence (OR = 1.89, g = 0.35; p < .05). Higher qualification of online counselors was not associated with efficacy. These findings extend and refine previous reports on guided and unguided online treatments.
Prognostic value of molecular response via ctDNA measurement in predicating response of systemic therapy in patients with advanced solid cancer.
Authors: Abdullah Esmail, Jian Guan, Jiaqiong Xu, Hadeel Al-Rawi, Bethany Parks, Noor Al Saadi, Tanya Khan, Laura Madoux, Marwa Taha, Maen Abdelrahim
Journal: Journal of Clinical Oncology (2022)

e13001 Background: Molecular profiling of cancer can guide treatment decision, monitor response and predict clinical outcome in the era of precision medicine and individualized treatment. Emerging evidence has suggested that ctDNA change correlates with treatment response and predates radiological relapse. Thus, we aim to provide real-world data regarding the dynamic changes of ctDNA level measured via Guardant 360 Response in advanced solid cancer correlates with clinical outcome. Methods: We retrospectively reviewed data of patients with advanced solid cancer and had at least 2 timepoints of Guardant 360 Response test at Houston Methodist Cancer center from 1/1/2014- 2 /1/2022. Data collected included age, gender, type of solid cancer, mutational values, treatment started date and type of systemic therapy. Personalized mutational profiles derived from tumor tissue via whole-exome sequencing were used to design patient-specific ctDNA assays for variant detection in plasma samples. Blood samples taken at baseline and 8 weeks were analyzed to a 70-gene next-generation sequencing panel. On-therapy changes in circulating tumor DNA levels (molecular response) were measured using a ratio computation, with response defined as a decrease in mean variant allele fraction of 50% or more. Apart from ctDNA analysis, patients were also monitored using tumor markers and radiological imaging. Results: : Of 267 patients, only 93 were met the inclusions criteria with age 58.66 (±12.95) and female were the most with 77 (82.80%). Patients with breast cancer were the dominant with 62 (66.67%), Lung adenocarcinoma 20 (21.51%), Uveal Melanoma 4 (4.30%), Colorectal Cancer and Lung Squamous Cell Carcinoma 2 (2.15 %) each, Large Cell Lung Carcinoma, Sarcoma and Thymic Carcinoma were 1(1.07%) each. Patients who received Chemotherapy /Immunotherapy were 38 (41.30%), Chemotherapy/Immunotherapy/Radiation therapy were 29 (31.52%), Immunotherapy 9 (9.78%), Chemotherapy/Immunotherapy/Targeted Therapy 2 (2.17%) and Targeted Therapy /Chemotherapy 3 (3.26%).Patients samples who correlated with clinical data were 89 (95.70%) and only 4 (4.30%) were not .Follow-up time 2.15 (interquartile range: 1.10-4.12) years, patients who still alive are 24 (25.81%), median survival time 2.4 (95% CI: 1.78-2.76) years. Conclusions: Our data demonstrated that molecular response evaluation using circulating tumor DNA as a noninvasive predictor of response to systemic therapy in addition to standard of care imaging in some solid cancer. Further prospective studies are needed to confirm the validation.
HGG-01. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes and promotion of the NOTCH pathway
Authors: Aalaa Abdallah, Herminio Cardona, Samantha Gadd, Daniel Brat, David Picketts, Oren Becher, Xiao-Nan Li
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Pediatric high-grade gliomas (pHGGs) are an aggressive CNS tumor which are often characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). A substitution of the Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described in a large cohort of pHGG samples and has been characterized as occurring in anywhere between 5-20% of pHGGs. Attempts to study the mechanisms of H3.3G34R have proven difficult due to the developmental nature of the disease and the requirement of co-occurring mutations for model development. METHODS: We utilized the RCAS system to develop a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the context of ATRX loss and ATRX presence in nestin expressing progenitors. RESULTS: We show that in H3.3G34R expressing mice, ATRX loss significantly increased tumor latency from 90 days to 143 days (p &amp;lt; 0.01, Log rank test) and decreased tumor incidence from 81% to 57% (p &amp;lt; 0.01, Fisher’s exact test). By contrast, H3.3G34R did not significantly impact tumor latency in either our ATRX loss (163 days to 143 days, p = 0.178, Log-rank test) or our ATRX expressing (95 days to 90 days, p = 0.415, Log-rank test) models. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates the PRC2 associated genes Hoxa2, Hoxa3, Hoxa5, and Hoxa7 (p &amp;lt; 0.05, unpaired t-test). GSEA analysis and RT-qPCR data suggest that ATRX loss works synergistically with H3.3G34R to promote NOTCH pathway activation through upregulation of the NOTCH ligand Dll3 (p &amp;lt; 0.01, unpaired t-test). CONCLUSIONS: Our study proposes a model in which ATRX loss is the major contributor to transcriptomic changes in the majority of H3.3G34R pHGGs. Broadly, our work highlights the importance of studying mechanisms of co-occurring genetic events separately and in combination.
Corrigendum to “Magnesium cationic cue enriched interfacial tissue microenvironment nurtures the osseointegration of gamma-irradiated allograft bone” [Bioact. Mater. 10C (April 2022) 32-47]
Authors: Wenhao Wang, Jie Shen, Yuan Meng, Miaoman Ye, Shaozhang Lin, Qi Zhao, Le Wang, Kenneth M.C. Cheung, Shuilin Wu, Yufeng Zheng, Xuanyong Liu, Paul K. Chu, Kelvin W.K. Yeung, Zhi-Yong Zhang
Journal: Bioactive Materials (2022)

[This corrects the article DOI: 10.1016/j.bioactmat.2021.08.027.].
HGG-05. Systematic review of diffuse hemispheric glioma, H3 G34-mutant and clinical factors influencing outcomes
Authors: Cameron Crowell, Daddy Mata-Mbemba, Julie Bennett, Kara Matheson, Michael Mackley, Craig Erker
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: A comprehensive description of clinical features and factors impacting prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (DHG H3G34) is not easily accessible. Understanding survival data and prognostic features is paramount for clinical advancements and ensuring patients/families are fully informed. METHODS: To summarize clinical, basic histomolecular, and treatment variables and their impacts on survival of DHG H3G34, a systematic review was undertaken. PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012, and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumour with at least one measure of survival or progression. A protocol was prospectively registered in PROSPERO (CRD42021267764) and PRISMA guidelines were followed. RESULTS: 27 studies met criteria for inclusion (13 pediatric-focused, 3 adult-focused, and 11 all ages). 135 unique patients with DHG H3G34 were included (118 G34R, 8 G34V, and 9 determined via methylation alone). Median age at diagnosis was 15.8 years (IQR=13.3-22.0). At presentation, 90% had localized disease. Co-occurring alterations included ATRX mutation 93%, TP53 mutation 88%, PDGFRA mutation 46%, PDGFRA amplification 13%, and MGMT promoter methylation in 70%. 89% of patients reported progressive disease with a median time-to-progression of 10.0 months. At last follow-up, 71% had died. Median time from progression to death was 5.0 months (IQR=3.0-12.0). Median overall survival was 17.3 months (95% CI 13.5-21.1) with a 1-, 2-, 3-, 5-year survival of 75, 39, 24, and 12%, respectively. Factors found to influence survival duration were presence of MGMT promoter methylation (HR=0.48, 95% CI 0.25-0.90) and less than near-total resection upfront (HR=3.59, 95% CI 2.07-6.22). CONCLUSION: This review highlights the poor prognosis, available survival measures, important prognostic features of DHG G34, and serves as a baseline for future clinical trials, though further study to identify prognostic biomarkers is needed.
The learning curve of radical nephrectomy for kidney cancer: Implications for surgical training
Authors: F. Belladelli, G. Rosiello, G. Fallara, G. Basile, G. Colandrea, D. Cignoli, A. Martini, W. Cazzaniga, G. Musso, F. Cei, D. Canibus, A. Ieva, C. Re, F. Dehò, A. Gallina, P. Karakiewicz, P. Rigatti, G. Guazzoni, A. Mottrie, F. Montorsi, R. Bertini, A. Briganti, A. Salonia, U. Capitanio, A. Larcher
Journal: European Urology (2022)
Possible role of the microbiota in urinary stones: A prospective study to correlate radiological density (Hounsfield Units) and cultural examination of urinary calculi
Authors: A.L. Pastore, Y. Al Salhi, A. Fuschi, A. Martoccia, S. Scalzo, P.P. Suraci, O.A. Rera, F.M. Valenzi, M.M. Maceroni, M. Rengo, A. Antonioni, A. Carbone
Journal: European Urology (2022)